Autism Spectrum Disorders (ASDs) are severe, life-long neurodevelopmental disorders that confer considerable impairment to individuals and a substantial burden to their families and communities. Little is known about the causes or correlates of ASDs. While diagnostic practices are improving ASD identification, relatively little high quality information is available about the phenotypic variation among ASD children, prevalence of co-morbid conditions, and risk factors for ASDs, some of which might be preventable. In response to growing concern as the number of children identified with autism increased, The Children's Health Act of 2000 mandated CDC to establish autism surveillance and research programs that address the magnitude, incidence, and causes of autism and related developmental disabilities. The Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDREs) were established at six national sites (California, Maryland, North Carolina, Pennsylvania, Colorado, and Georgia) to fulfill this mandate and are currently carrying out the Study to Explore Early Development (SEED), a population-based case-control study. SEED will address hypotheses including: ASD phenotypic variation, including the pattern of clustering of core symptoms, timing of onset, cognitive status, and presence of medical and psychiatric co-morbidities; gastrointestinal features; genetic variation and interaction with environmental risk factors (GxE); infection, immune function, and autoimmunity factors; hormonal factors and maternal reproductive characteristics; and sociodemographic and lifestyle factors. Data collection includes developmental assessments and extensive data on the pre- and perinatal health and environment of the children and their parents via interviews, medical record review, self-administered questionnaires, and biologic samples. Data collection is still ongoing, but as of December 2010, SEED had completed data collection on 1435 children and their families - 350 with ASD, 534 with other neurodevelopmental disorders, and 551 population controls. This proposal seeks to carry out SEED Phase II, recruiting another 1080 children in each study group across the national sites to address hypotheses in five domains: 1) ASD phenotype, 2) infection and immune function, including autoimmunity, 3) reproductive and hormonal features, 4) genetic features, and 5) sociodemographic features. The increased combined sample size will enable well-powered assessment of these hypotheses, particularly for phenotypic subgroups and GxE interactions. Given the experience of SEED I and the infrastructure in place at each CADDRE site, SEED II can be quickly implemented, creating a combined SEED sample of clinical, risk factor, and biological specimens and data on over 3600 families. The combined SEED study will be the largest study of ASD of this kind and is poised to make significant contributions to our understanding of the complex autism phenotype and to identify potential risk factors for autism that deserve more detailed attention in clinical and public health practice to reduce the impact of ASDs.